title: NCX3 regulates mitochondrial Ca(2+) handling through the AKAP121-anchored signaling complex and prevents hypoxia-induced neuronal death.
abstract: The mitochondrial influx and efflux of Ca(2+) play a relevant role in cytosolic and mitochondrial Ca(2+) homeostasis, and contribute to the regulation of mitochondrial functions in neurons. The mitochondrial Na(+)/Ca(2+) exchanger, which was first postulated in 1974, has been primarily investigated only from a functional point of view, and its identity and localization in the mitochondria have been a matter of debate over the past three decades. Recently, a Li(+)-dependent Na(+)/Ca(2+) exchanger extruding Ca(2+) from the matrix has been found in the inner mitochondrial membrane of neuronal cells. However, evidence has been provided that the outer membrane is impermeable to Ca(2+) efflux into the cytoplasm. In this study, we demonstrate for the first time that the nuclear-encoded NCX3 isoform (1) is located on the outer mitochondrial membrane (OMM) of neurons; (2) colocalizes and immunoprecipitates with AKAP121 (also known as AKAP1), a member of the protein kinase A anchoring proteins (AKAPs) present on the outer membrane; (3) extrudes Ca(2+) from mitochondria through AKAP121 interaction in a PKA-mediated manner, both under normoxia and hypoxia; and (4) improves cell survival when it works in the Ca(2+) efflux mode at the level of the OMM. Collectively, these results suggest that, in neurons, NCX3 regulates mitochondrial Ca(2+) handling from the OMM through an AKAP121-anchored signaling complex, thus promoting cell survival during hypoxia.
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples-National Institute of Neuroscience, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Scorziello
authors.forename: Claudia
authors.initials: C
authors.lastname: Savoia
authors.forename: Maria Josè
authors.initials: MJ
authors.lastname: Sisalli
authors.forename: Annagrazia
authors.initials: A
authors.lastname: Adornetto
authors.forename: Agnese
authors.initials: A
authors.lastname: Secondo
authors.forename: Francesca
authors.initials: F
authors.lastname: Boscia
authors.forename: Alba
authors.initials: A
authors.lastname: Esposito
authors.forename: Elena V
authors.initials: EV
authors.lastname: Polishchuk
authors.forename: Roman S
authors.initials: RS
authors.lastname: Polishchuk
authors.forename: Pasquale
authors.initials: P
authors.lastname: Molinaro
authors.forename: Annalisa
authors.initials: A
authors.lastname: Carlucci
authors.forename: Luca
authors.initials: L
authors.lastname: Lignitto
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.forename: Antonio
authors.initials: A
authors.lastname: Feliciello
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D004285:Dogs; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021381:Protein Transport; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000502:physiology*
chemical_list: D054758:A Kinase Anchor Proteins; C486333:Akap1 protein, mouse; C491101:Slc8a3 protein, mouse; D019831:Sodium-Calcium Exchanger; D002118:Calcium
keywords: AKAP1; AKAP121; Ca2+ flux; Mitochondria; NCX3